Many therapeutic substances are sensitive to environmental influences and due to these impacts their active forms are transformed to degradation products which are often less effective than the active forms. Apart from lower efficacy, degradation products may also cause undesirable effects thus affecting safe use of a medicament. Already a very low percent of impurities or degradation products of the active substance may significantly impair a drug safety. Therefore, it is important that therapeutic substance is as pure as possible when administered, that is, the percent of degradation products and impurities should be minimal.
Procedures for the preparation of an active substance per se (e.g., processes of isolation and purification), and interim phases of storage of the active substance and/or its intermediates during the production and the phases of storage of the active substance up to the procedure and during the course of pharmaceutical dosage form production have an influence on the percent of impurities and degradation products of the active substance. At the same time, pharmaceutical excipients comprised in the pharmaceutical dosage form have an influence on the percent of degradation products and impurities in the active substance. Said pharmaceutical excipients are selected from the group consisting of fillers or diluents, binders, lubricants, glidants, disintegrants, colorants, flavors, adsorbents, plasticizers and the like.
Not only an active substance undergoes degradation by environmental influences but also excipients in a pharmaceutical dosage form may be degraded. Degradation products of the latter act as the reactive sites which trigger degradation reactions of the active substance in a pharmaceutical dosage form.
Among the environmental factors which have an impact on an active substance are, for example, temperature, humidity, light, (e.g. UV light) and gases, present in the environment such as, e.g., oxygen or carbon dioxide. An important factor is also the pH environment, that is, presence of substances which have influence on acidity or alkalinity of the environment (e.g., acids, alkalis, salts, metal oxides) and the reactivity of the ambient medium or active substance (free radicals, heavy metals), etc.
The majority of therapeutic active substances are sensitive to temperature, in particular high temperature. Temperature increase accelerates chemical reactions and thus more degradation products are formed in a shorter period of time. In certain cases at elevated temperature the reactions take place which would not at normal temperature. Thus, the temperature has an impact on the kinetic and thermodynamic parameters of the chemical reactions leading to occurrence of degradation products.
Many active substances are sensitive to humidity. At increased humidity water is bound to the active substance itself and/or pharmaceutical excipients surrounding the active substance. Water associated with one or more other environmental influences may thus triggers degradation reactions of the active substance. For example, substances known in the prior art to be sensitive to humidity are:                β-lactamase inhibitor potassium clavulanate (Finn, M. J. et al, J. Chem. Soc. Perkin. Trans 1, 1984, 1345-349; Haginaka J. et al, Chem. Pharm. Bull. 29, 1981, 3334-3341; Haginaka J. et al, Chem. Pharm. Bull. 33, 1985, 218-224);                    proton pump inhibitors such as, e.g. omeprazole, lansoprazole and pantoprazole (Kristl, A. et al, Drug. Dev. Ind. Pharm. 26 (7), 2000, 781-783; Ekpe, A. et al, Drug. Dev. Ind. Pharm. 25 (9), 1999, 1057-065);            HGM-CoA reductase inhibitors, e.g. pravastatin and atorvastatin.                        
Compounds containing structural elements which at low pH are converted to a lactone form are generally sensitive to an acidic environment. Among them the best known are HGM-CoA reductase inhibitors (statins) and related compounds which comprise 7-substituted-3,5-dihydroxyheptanoic and/or 7-substituted-3,5-dihydroxyheptanoic acid groups. Apart from conversion to a lactone form, other mechanisms of degradation of said active substances may take place in an acidic environment, for example, isomerization in case of pravastatin. (Serrajuddin, A. T. M. et al, Biopharm. Sci. 80, 830-834, 1991; Kearney, A. S. et al, Pharm. Res. 10, 1993, 1461-1465).
Statins and related compounds are in the form of a cyclic ester—lactone, therefore, among others they are also sensitive to an alkaline medium, where they are transformed to an acid form.
Compounds in the environment which increase acidity or alkalinity of the environment trigger degradation reactions of an active substance sensitive to acidic or alkaline environment. Carbon dioxide in the presence of humidity or water, in which it is freely soluble, forms carbonic acid which increases the acidity of the environment.
Light and in particular UV light induces degradation reactions of active substances, especially organic ones. It is known that among others levofloxacin (Sato, Y. Y. E. and Moroi, R., Arzneim, Forsch./Drug Res. 43, 1993, 601-606) and atorvastatin are also sensitive to light (Hurley, T. R. et al, Tetrahedron 49, 1993, 1979-1984).
Oxygen induces oxidation, that is, oxidative degradation reactions of an active substance and/or pharmaceutical excipients resulting in formation of the reactive sites and/or degradation products which lead to further oxidation or further oxidative degradation reactions of the active substance and/or pharmaceutical excipients. For example, active substances known in the prior art to be sensitive to oxidation are:                Captopril, chlorpromazine, morphine, L-ascorbic acid, vitamin E, phenylbutazone and tetracyclines (Waterman, K. C., et al, in “Stabilization of Pharmaceuticals to Oxidative Degradation”, Pharmaceutical Development and Technology, 7(1), 2002, 1-32);        Omeprazole; and        HGM-CoA reductase inhibitors, e.g. pravastatin, atorvastatin, simvastatin and lovastatin (Javernik, S., et al, Pharmazie 56, 2001, 738-740; Smith, G. B., et al, Tetrahedron 49, 1993, 4447-4462; patent application P-200200244).        
HMG-CoA reductase inhibitors (statins) are also among the active substances sensitive to pH of the environment, humidity, light, temperature, carbon dioxide and oxygen. They are known as the most effective therapeutically active substances for the treatment of dyslipidemias and cardiovascular disease, selected from the group consisting of dyslipidemia, hyperlipidemia, hypercholesterolemia, atherosclerosis, arteriosclerosis, coronary artery diseases, coronary heart disease and the like, associated with the metabolism of lipids and cholesterol. The mechanism of action of statins is the inhibition of the biosynthesis of cholesterol and other sterols in the liver of humans or animals. They are competitive inhibitors of HMG-CoA reductase or 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, an enzyme which catalyses the conversion of HMG-CoA to mevalonate in the liver of humans or animals, which is an important step in the biosynthesis of cholesterol in the liver. Recent studies indicate that, in addition to the said therapeutic effects, statins also have other therapeutic effects and thus they are useful for the treatment of diseases, abnormal conditions and disorders which are selected from the group consisting of vascular disorders, inflammatory disease, allergic disease, neurodegenerative disease, malignant disease, viral disease (WO 0158443), abnormal bone states, (WO 0137876), amyloid-β precursor protein processing disorders such as Alzheimer's disease or Down's Syndrome (WO 0132161).
Among the statins, for example, the following are known: pravastatin, atorvastatin simvastatin, lovastatin, mevastatin or compactin, fluvastatin or fluindostatin, cer(i)vastatin or rivastatin, rosuvastatin or visastatin, and itavastatin or pitavastatin, or nisvastatin.
Pravastatin is chemically (betaR*,deltaR,1S,2S,6S,8S,8aR)-1,2,6,8,8a-hexahydro-beta, delta, 6-trihydroxy-2-methyl-8-((2S)-2-methyl-1-oxobutoxy)-1-naphthalene heptanoic acid. A sodium salt of said acid is sodium pravastatin. It was described first time in U.S. Pat. No. 4,346,227.
Atorvastatin is chemically a (R-(R*,R*))-2-(4-fluorophenyl-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid hemicalcium salt. It was described first time in U.S. Pat. No. 5,273,995.
Rosuvastatin is chemically (2:1) (3R,5S,6E)-7-(4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methyl(metylsulfonyl)amino)-5-pyrimidinyl)-3,5-dihydroxy-6-heptenoic acid calcium salt. It was described first time in U.S. Pat. No. 5,260,440.
Fluvastatin is chemically R*,S*-(E)-(+-7-(3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl)-3,5-dihydroxy-6-heptenoic acid. Fluvastatin sodium is a sodium salt of said acid. It was described first time in European patent 114027.
Simvastatin is chemically (1S-(1alpha,3alpha,7beta,8beta(2S*,4S*)8abeta))-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyrran-2-il)ethyl)-1-naphthalenyl-2,2-dimetylbutanoate. It was described first time in U.S. Pat. No. 4,444,784.
Lovastatin is chemically (1S-(1alpha,3alpha,7beta,8beta(2S*,4S*)8a beta))-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-(2-(tetrahydro-4-hydroxy-6-oxo-2H-pyrran-2-yl)ethyl)-1-naphthalenyl-2-methylbutanoate. It was described first time in U.S. Pat. No. 4,231,938 and JP 8425599.
Itavastatin is chemically (S-(R*,S*-(E)))-7-(2-cyclopropyl-4-(4-fluorophenyl)-3-quinolynyl)-3,5-dihydroxy-6-heptenoic acid. Pitavastatin is a lactone form of itavastatin. They were described first time in European patent no. 304063 and U.S. Pat. No. 5,011,930, respectively.
Mevastatin is chemically (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S,8aR)-2-methyl-8-((2S)-2-methylbutanoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoic acid. It was described first time U.S. Pat. No. 3,983,140.
Cerivastatin is chemically (S-(R*,S*-(E)))-7-(4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(1-methylethyl)-3-pyridinyl)-3,5-dihydroxy-6-heptanoic acid. It was described first time in European patent no. 491226.
Many of the above statins are sensitive in particular to environmental influences, for example, atmospheric influences and pH of the environment. In the prior art it is known that certain statins are sensitive to acidic environment (low pH values) wherein they are degraded to their lactone forms and different isomers. For example, pravastatin, atorvastatin, itavastatin, and fluvastatin are converted to their lactone forms in an acidic environment.
In the prior art it is also known that statins which are in the lactone form, e.g. lovastatin and simvastatin, are sensitive to alkaline environment wherein they are converted to the acid form.
The sensitivity of different pharmaceutical active substances to oxidative degradation is described by Waterman, K. C., et al, in “Stabilization of Pharmaceuticals to Oxidative Degradation”, Pharmaceutical Development and Technology, 7(1), 2002, 1-32, and possible approaches to stabilize pharmaceutical active substances against oxidative degradation are also presented. The above mentioned article suggests that study of oxidative mechanism in solid pharmaceutical dosage forms is difficult and demanding as indicated by few reports in said area. An active substance per se and more frequently an active substance in a pharmaceutical dosage form may oxidize. During the processing of drug to form a solid dosage form, it is possible to mechanically generate amorphous drug. The percent of formed amorphous form is usually small and below 1%. Amorphous drug regions have greater mobility and lack crystal-lattice stabilization energy, and as a result oxygen permeability and solubility will be higher. Greater mobility and higher oxygen concentration present in amorphous active substance also facilitate electron transfer to oxygen. (Waterman, K. C., et al, Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7(1), 2002, 1-32).
Byrn, S. R., et al. (Solid-State Chemistry of Drugs, 2nd Ed., SSCI, West Lafayette, 1999) disclose that molecular oxygen from atmosphere reacts with organic crystals and said reactivity depends on a crystal form and morphology, respectively, which determines permeability to oxygen and its solubility in the crystal lattice. In some examples the reactivity decreases with increased melting point indicating that higher crystalline lattice energy inhibits diffusion of oxygen.
It is in general more difficult to remove an electron from a drug when it is more positively charged. Therefore drug stability against oxidation is often greater under lower pH conditions. The sensitivity of an active substance to oxidation also depends on a pharmaceutical dosage form per se and pharmaceutical excipients in it. Pharmaceutical excipients also influence oxidation of the active substance in a pharmaceutical dosage form. They can potentially solvate some of the active substances either directly or by bringing in low levels of moisture. In a solid solution form, the active substance will be amorphous with all the corresponding reactivity discussed above. Excipients themselves can be a source of oxidants or metals (e.g. present impurities) and may be involved in occurrence of mobile oxidative species, such as peroxyl radicals, superoxide and hydroxyl radicals. This depends on the hydrogen bond strength of the excipient and whether there are good electron donor sites (e.g. amines). Peroxide impurities are often present in polymeric excipients and they are a major source of oxidation in pharmaceutical formulations. (Waterman, K. C., et al, Stabilization of Pharmaceuticals to Oxidative Degradation, Pharmaceutical Development and Technology, 7(1), 2002, 1-32).
In the studies we have found that some of the above statins are particularly sensitive to oxidation. Among them particularly sensitive are certain polymorphic or amorphous forms of atorvastatin, pravastatin, lovastatin, simvastatin and rosuvastatin.
The influence of oxygen on occurrence of degradation products of amorphous and four polymorphic forms of atorvastatin was investigated. The samples of amorphous atorvastatin and polymorphic forms I to IV of atorvastatin were exposed at 80° C. in normal (air) and oxygen atmosphere for 3 days. The assay of oxidation products was determined by liquid chromatography. All of the chosen forms of atorvastatin stored at 4° C. were analyzed as the reference samples.
TABLE 1Increase of the degradation products of amorphous and differentcrystalline forms of atorvastatin stored at 80° C. in normal (air)and oxygen atmosphere for 3 days in respect to reference samplesIncrease ofAmor-degradationphousCrystallineCrystallineCrystallineCrystallineproducts %ATVform Iform IIform IIIform IVAIR1.040.040.250.111.14OXYGEN3.40.070.710.473.67
The above study shows that different forms of atorvastatin are variably sensitive to the impact of oxygen regarding the formation of degradation products. In case of amorphous atorvastatin and crystalline form IV the percent of oxidation degradation products essentially increased in oxygen atmosphere and normal atmosphere (air). In case of crystalline forms I, II and III the percent of oxidation degradation products was low in air atmosphere, while in oxygen atmosphere the percent of oxidation degradation products increased in crystalline forms II and III.
We can conclude that crystalline form I is stable to oxygen and oxidation, crystalline forms II and III are slightly sensitive to oxidation and crystalline form IV and amorphous atorvastatin are highly sensitive to oxidation.